Department of Medicine, Tufts Medical Center, Molecular Oncology Research Institute, Tufts University Medical School, Boston, Massachusetts 02111, USA.
Cancer Res. 2010 Jul 15;70(14):5880-90. doi: 10.1158/0008-5472.CAN-09-4341. Epub 2010 Jun 22.
Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies that block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown that matrix metalloprotease-1 (MMP1) activation of the G protein-coupled receptor protease-activated receptor-1 (PAR1) is an important stimulator of angiogenesis and metastasis in peritoneal mouse models of ovarian cancer. In the present study, we tested the hypothesis that MMP1-PAR1 promotes angiogenesis through its paracrine control of angiogenic chemokine receptors. We found that MMP1-PAR1 activation induces the secretion of several angiogenic factors from ovarian carcinoma cells, most prominently interleukin (IL)-8, growth-regulated oncogene-alpha (GRO-alpha), and monocyte chemoattractant protein-1. The secreted IL-8 and GRO-alpha acts on endothelial CXCR1/2 receptors in a paracrine manner to cause robust endothelial cell proliferation, tube formation, and migration. A cell-penetrating pepducin, X1/2pal-i3, which targets the conserved third intracellular loop of both CXCR1 and CXCR2 receptors, significantly inhibited endothelial cell proliferation, tube formation, angiogenesis, and ovarian tumor growth in mice. Matrigel plugs mixed with MMP1-stimulated, OVCAR-4-conditioned media showed a dramatic 33-fold increase in blood vessel formation in mice. The X1/2pal-i3 pepducin completely inhibited MMP1-dependent angiogenesis compared with a negative control pepducin or vehicle. Conversely, a vascular endothelial growth factor-directed antibody, Avastin, suppressed angiogenesis in mice but, as expected, was unable to inhibit IL-8 and GRO-alpha-dependent endothelial tube formation in vitro. These studies identify a critical MMP1-PAR1-CXCR1/2 paracrine pathway that might be therapeutically targeted for ovarian cancer treatment.
卵巢癌是一种致命的妇科恶性肿瘤，可能受益于新的治疗方法，这些方法可以阻断肿瘤-基质相互作用和肿瘤血管生成中涉及的关键旁分泌途径。最近的研究表明，基质金属蛋白酶-1（MMP1）激活 G 蛋白偶联受体蛋白酶激活受体-1（PAR1）是促进腹膜小鼠卵巢癌模型中血管生成和转移的重要刺激因素。在本研究中，我们测试了 MMP1-PAR1 通过旁分泌控制血管生成趋化因子受体促进血管生成的假设。我们发现，MMP1-PAR1 激活可诱导卵巢癌细胞分泌多种血管生成因子，其中最主要的是白细胞介素（IL）-8、生长调节癌基因-α（GRO-α）和单核细胞趋化蛋白-1。分泌的 IL-8 和 GRO-α 以旁分泌方式作用于内皮细胞 CXCR1/2 受体，引起内皮细胞的强烈增殖、管形成和迁移。一种穿透细胞的肽聚糖，X1/2pal-i3，靶向 CXCR1 和 CXCR2 受体的保守第三细胞内环，可显著抑制内皮细胞增殖、管形成、血管生成和小鼠卵巢肿瘤生长。与 MMP1 刺激的 OVCAR-4 条件培养基混合的 Matrigel 塞在小鼠中显示出血管形成的急剧增加 33 倍。与阴性对照肽聚糖或载体相比，X1/2pal-i3 肽聚糖完全抑制 MMP1 依赖性血管生成。相反，血管内皮生长因子导向抗体 Avastin 抑制了小鼠的血管生成，但正如预期的那样，它无法抑制体外 IL-8 和 GRO-α 依赖性内皮管形成。这些研究确定了一个关键的 MMP1-PAR1-CXCR1/2 旁分泌途径，该途径可能是治疗卵巢癌的治疗靶点。
